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INTRODUCTION: Nutrient deficiency and immune and inflammatory disturbances in early life may compromise neurodevelopment and be implicated in the aetiology of psychiatric disorders. However, current evidence is limited by its predominantly observational nature. COpenhagen Prospective Study on Neuro-PSYCHiatric Development (COPSYCH) is a research alliance between Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research with the overall aim to investigate effects of prenatal and early life exposures on neurodevelopment at 10 years. COPSYCH will investigate the impact of prenatal n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) and high-dose vitamin D supplementation on neurodevelopment reflected by brain development, neurocognition and psychopathology. Moreover, the neurodevelopmental impact of early life exposures such as infections, low grade inflammation and the gut microbiome will be scrutinised. METHODS AND ANALYSIS: COPSYCH is based on the prospective and ongoing COPSAC2010 birth cohort of 700 mother-child pairs. Randomised controlled trials of supplementation with n-3 LCPUFA and/or high-dose vitamin D or placebo in the third trimester were embedded in a factorial 2×2 design (ClinicalTrials.gov: NCT01233297 and NCT00856947). This unique cohort provides deep phenotyping data from 14 previous clinical follow-up visits and exposure assessments since birth. The ongoing 10-year visit is a 2-day visit. Day 1 includes a comprehensive neurocognitive examination, and assessment of psychopathological dimensions, and assessment of categorical psychopathology. Day 2 includes acquisition of brain structural, diffusion and functional sequences using 3 Tesla MRI. Study outcomes are neurocognitive, psychopathological and MRI measures. ETHICS AND DISSEMINATION: This study has been approved by the Danish National Committee on Health Research Ethics and The Danish Data Protection Agency.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

BACKGROUND: Pregnant women have an elevated risk of illness and hospitalisation from influenza. Pregnant women are recommended to be prioritised for influenza vaccination during any stage of pregnancy. The risk of seasonal influenza varies substantially throughout the year in temperate climates; however, there is limited knowledge of how vaccination timing during pregnancy impacts the benefits received by the mother and foetus. OBJECTIVES: To compare antenatal vaccination timing with regard to influenza vaccine immunogenicity during pregnancy and transplacental transfer to their newborns. METHODS: Studies were eligible for inclusion if immunogenicity to influenza vaccine was evaluated in women stratified by trimester of pregnancy. Haemagglutination inhibition (HI) titres, stratified by trimester of vaccination, had to be measured at either pre-vaccination and within one month post-vaccination, post-vaccination and at delivery in the mother, or in cord/newborn blood. Authors searched PubMed, Scopus, Web of Science and EMBASE databases from inception until June 2016 and authors of identified studies were contacted for additional data. Extracted data were tabulated and summarised via random-effect meta-analyses and qualitative methods. RESULTS: Sixteen studies met the inclusion criteria. Meta-analyses found that compared with women vaccinated in an earlier trimester, those vaccinated in a later trimester had a greater fold increase in HI titres (1.33- to 1.96-fold) and higher HI titres in cord/newborn blood (1.21- to 1.64-fold). CONCLUSIONS: This review provides comparative analysis of the effect of vaccination timing on maternal immunogenicity and protection of the infant that is informative and relevant to current vaccine scheduling for pregnant women.

The reporting of the first draft of the human genome in 2000 brought with it much hope for the future in what was felt as a paradigm shift toward improved health outcomes. Indeed, we have now mapped the majority of variation across human populations with landmark projects such as 1000 Genomes; in cancer, we have catalogued mutations across the primary carcinomas; whilst, for other diseases, we have identified the genetic variants with strongest association. Despite this, we are still awaiting the genetic revolution in healthcare to materialise and translate itself into the health benefits for which we had hoped. A major problem we face relates to our underestimation of the complexity of the genome, and that of biological mechanisms, generally. Fixation on DNA sequence alone and a 'rigid' mode of thinking about the genome has meant that the folding and structure of the DNA molecule -and how these relate to regulation- have been underappreciated. Projects like ENCODE have additionally taught us that regulation at the level of RNA is just as important as that at the spatiotemporal level of chromatin.In this review, we chart the course of the major advances in the biomedical sciences in the era pre- and post the release of the first draft sequence of the human genome, taking a focus on technology and how its development has influenced these. We additionally focus on gene editing via CRISPR/Cas9 as a key technique, in particular its use in the context of complex biological mechanisms. Our aim is to shift the mode of thinking about the genome to that which encompasses a greater appreciation of the folding of the DNA molecule, DNA- RNA/protein interactions, and how these regulate expression and elaborate disease mechanisms.Through the composition of our work, we recognise that technological improvement is conducive to a greater understanding of biological processes and life within the cell. We believe we now have the technology at our disposal that permits a better unde

Background Systemic low-grade inflammation has been demonstrated in a range of the frequent noncommunicable diseases (NCDs) proposing a shared mechanism, but is largely unexplored in relation to allergic sensitization. We therefore aimed to investigate the possible association with childhood allergic sensitization. Methods High-sensitivity C-reactive protein (hs-CRP), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and chemokine (C-X-C motif) ligand 8 (CXCL8) were measured in plasma at age 6 months (N = 214) and 7 years (N = 277) in children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) birth cohort. Allergic sensitization against common inhalant and food allergens was determined longitudinally at ages ½, 1½, 4 and 6 years by specific IgE assessments and skin prick tests. Associations between inflammatory biomarkers and sensitization phenotypes were tested with logistic regression and principal component analyses (PCAs). Results Adjusted for gender, recent infections, and a CRP genetic risk score, hs-CRP at 7 years was associated with concurrent elevated specific IgE against any allergen [adjusted OR (aOR) = 1.40; 95% CI, 1.14–1.72; P = 0.001], aeroallergens (aOR, 1.43; 1.15–1.77; P = 0.001), food allergens (aOR, 1.31; 95% CI, 1.02–1.67; P = 0.04), sensitization without any clinical allergy symptoms (aOR = 1.40; 1.06–1.85; P = 0.02), and with similar findings for skin prick tests. The other inflammatory markers were not univariately associated with sensitization, but multiparametric PCA suggested a specific inflammatory response among sensitized children. Inflammatory markers at age 6 months were not associated with subsequent development of sensitization phenotypes. Conclusions Elevated hs-CRP is associated with allergic sensitization in school-aged children suggesting systemic low-grade inflammation as a phenotypic characteristic of this early-onset NCD.

RATIONALE: Allergen exposure is associated with the development of allergic sensitization in childhood as reflected by global variations in sensitization patterns. However, there is little evidence to support a direct association.OBJECTIVES: To investigate the association between perinatal aeroallergen exposure and sensitization and rhinitis to such allergens later in childhood.METHODS: Allergic sensitization to cat, dog, and house dust mites was diagnosed longitudinally using skin prick tests and specific IgE measurements at ½, 1½, 4, 6, and 13 years in 399 children from the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort. Rhinitis was diagnosed at 7 and 13 years. Allergen exposure was defined as dog or cat in the home during the 3rd trimester of pregnancy or the first year of life and as allergen levels of dog, cat, and house dust mite in bed dust samples at 1 year. Associations between exposure and outcomes were analyzed by logistic regression and stratified for eczema status and test method (skin prick test and specific IgE).RESULTS: We found no association between dog or cat exposure in perinatal life and sensitization or rhinitis during childhood. Similarly, there was no association between levels of allergens in bed dust samples and sensitization or rhinitis during childhood.CONCLUSION: Perinatal indoor aeroallergen exposure does not seem to affect development of allergic sensitization or rhinitis during childhood questioning the relevance of allergen avoidance as a preventive measure. Other factors such as timing of allergen exposure or other environmental adjuvants may contribute in a more complex pathway to sensitization.

AIM: Prescription of inhaled corticosteroids to children with asthma is recommended at half the nominal dose of adults in order to reduce the risk of systemic side effects. However, there is a lack of pharmacokinetic trials supporting such dose reduction regimens. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed dose combination of beclometasone-dipropionate (BDP) and formoterol after dry powder inhaler (DPI) administration in children, adolescents and adults.METHODS: The pharmacokinetic profiles of formoterol and beclometasone-17-monopropionate (B17MP; active metabolite of BDP) were evaluated over 8 h from two independent studies comprising children (6-11yrs, n = 27), adolescents (12-17 yrs, n = 28) and adults (≥18 yrs, n = 30) receiving a single, fixed dose of BDP/formoterol (children: 200 μg/24 μg, adolescents and adults: 400 μg/24 μg) via DPI.RESULTS: The systemic exposure (AUC) for children versus adults was almost doubled for formoterol and similar for B17MP despite the halved BDP dose administered in children. In adolescents the AUC for formoterol and B17MP were approximately one third higher than in adults for both compounds. Upon normalization for the BDP/formoterol dose in the three populations the AUC and peak concentration (C(max)) correlated inversely with age and body surface area of the patients (r ≤ -0.53; p < 0.0001).CONCLUSION: The systemic exposure to the active ingredients of BDP/formoterol administered as DPI correlates inversely with age and body size suggesting that dry powder dosage regimens should be adjusted for age and body size to avoid high systemic drug levels in children.

Background Early-life immune deviation is suspected in the inception of atopic disease. Objective To investigate the association between cord blood chemokines and the subsequent development of atopic biomarkers and clinical end-points during the first 6 years of life. Methods The Th1-associated chemokines CXCL10 and CXCL11 and the Th2-associated chemokines CCL17 and CCL22 were assessed in cord blood of asymptomatic at-risk newborn children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC2000) birth cohort and associated with the longitudinal development of biomarkers and clinical end-points of asthma, eczema, and allergic rhinitis during the first 6 years of life. Results Cord blood CCL22 levels were significantly associated to total-IgE levels measured at four time-points during the first 6 years of life; overall odds ratio, 1.54 [CI, 1.25–1.89; P < 0.0001]. CXCL10 and CXCL11 were not associated with development of any atopic disorders or biomarkers. Conclusion and Clinical Relevance High cord blood levels of the Th2 related chemokine CCL22 were significantly associated with high total- IgE levels during the first 6 years of life, but not with specific sensitization, asthma, eczema or allergic rhinitis. This suggests an inborn skewing of the immune system in healthy newborns developing elevated total- IgE later in life., Funding Agencies|Lundbeck Foundation||The Danish Strategic Research Council||Pharmacy Foundation||Augustinus Foundation||Danish Medical Research Council||The Danish Pediatric Asthma Centre||Swedish Research Council|K2011-56X-21854-01-06|Cancer and Allergy Association||Olle Engk-vist Foundation

Childhood otitis media with effusion is a common disease and a link to allergic diseases has been suggested.

Udgivelsesdato: 2009-Oct, BACKGROUND: Allergic and nonallergic rhinitis are common childhood disorders. OBJECTIVE: To study nasal eosinophilia and nasal airway patency in young children with allergic and nonallergic rhinitis to assess the pathology behind such diagnoses. METHODS: We investigated 255 children at six years of age from the Copenhagen Prospective Study on Asthma in Childhood birth cohort assessing rhinitis history, specific immunoglobulin E relevant to rhinitis symptoms, nasal eosinophilia and nasal airway patency by acoustic rhinometry before and after decongestion. Associations were studied in a multivariate graphical model corrected for gender, height and nasal steroid usage. RESULTS: Allergic rhinitis was significantly and directly associated with irreversible nasal airway obstruction (reduced decongested nasal airway patency) (P = 0.004), whereas nonallergic rhinitis was not. Both allergic rhinitis (P = 0.000) and nonallergic rhinitis (P = 0.014) were directly and significantly associated with nasal eosinophilia, but this association was stronger for allergic rhinitis. CONCLUSION: Allergic rhinitis and nonallergic rhinitis are of different pathologies as suggested from their different associations not only to allergy but importantly also to irreversible nasal airway obstruction and eosinophilic inflammation. Allergic rhinitis was significantly associated with nasal eosinophilia and irreversible nasal airway obstruction suggesting chronic inflammation and structural remodeling of the nasal mucosa in children at the age of 6 years. Nonallergic rhinitis exhibited no change in the nasal airway patency, but some nasal mucosal eosinophilia albeit less than children with allergic rhinitis.